肥胖诱导的 ZBTB7A 上调通过 SREBP1 促进脂质积累。
Obesity-Induced Upregulation of ZBTB7A Promotes Lipid Accumulation through SREBP1.
机构信息
Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361000, China.
出版信息
Biomed Res Int. 2020 Jan 7;2020:4087928. doi: 10.1155/2020/4087928. eCollection 2020.
OBJECTIVE
Nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases. However, the pathogenesis of NAFLD is not still unclear. This study aims at evaluating the role of zinc finger and BTB domain-containing 7A (ZBTB7A) in NAFLD.
METHODS
Western blotting, real-time reverse transcription PCR (RT-PCR), and immunohistochemistry were submitted to evaluate the level of ZBTB7A in the high fatty diet- (HFD-) induced NAFLD mouse model. , the expression of ZBTB7A was assessed in oleic acid- (OA-) induced HepG2 cells with western blotting and RT-PCR. The luciferase reporter assay was used to estimate the effect of ZBTB7A on the SREBP1 and NF-B, and the ChIP assay was subjected to evaluate the direct binding to the SREBP1 promoter. Oil Red staining was used to detect lipid accumulation, and the ELISA was used to verify the levels of TG, T-CHO, and MDA. ZBTB7A was knocked down with siRNA, and RT-PCR was performed to analyze the lipogenesis-, fatty acid transporter-, and oxidation metabolism-related genes expression. The levels of ZBTB7A in primary hepatocyte, Kupffer, and hepatic stellate cells (HSCs) were tested by RT-PCR.
RESULTS
The upregulation of ZBTB7A expression was assessed in NAFLD mice, and ZBTB7A expression was positively correlated with TNF, IL-6, TG, T-CHO, and MDA. ZBTB7A was highly expressed in the hepatocytes. , OA-induced ZBTB7A expression and ZBTB7A expression were closely associated with SREBP1c. ZBTB7A could activate the promoter activity of SREBP1 and activate NF-B activity. Interestingly, the direct binding of ZBTB7A in the SREBP1 promoter was acquired in HepG2 cells. Inhibition of ZBTB7A expression could attenuate OA-induced lipid accumulation, inhibit the expression of the lipogenesis-related genes and fatty acid transporter genes, and promote the expression of oxidation metabolism-related genes.
CONCLUSION
ZBTB7A plays a significant role in the development process of NAFLD, and obesity-induced upregulation of ZBTB7A promotes lipid accumulation through activation of SREBP1 and NF-B. ZBTB7A may be a potential novel target for the therapy of NAFLD.
目的
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病之一。然而，NAFLD 的发病机制尚不清楚。本研究旨在评估锌指和 BTB 结构域蛋白 7A（ZBTB7A）在 NAFLD 中的作用。
方法
采用 Western blot、实时逆转录 PCR（RT-PCR）和免疫组织化学方法检测高脂肪饮食（HFD）诱导的 NAFLD 小鼠模型中 ZBTB7A 的水平。用 Western blot 和 RT-PCR 检测油酸（OA）诱导的 HepG2 细胞中 ZBTB7A 的表达。用荧光素酶报告基因检测 ZBTB7A 对 SREBP1 和 NF-B 的影响，用 ChIP 检测法评估其对 SREBP1 启动子的直接结合。油红染色检测脂质积聚，ELISA 检测 TG、T-CHO 和 MDA 水平。用 siRNA 敲低 ZBTB7A，用 RT-PCR 分析脂肪生成、脂肪酸转运和氧化代谢相关基因的表达。用 RT-PCR 检测原代肝细胞、库普弗细胞和肝星状细胞（HSCs）中 ZBTB7A 的水平。
结果
在 NAFLD 小鼠中检测到 ZBTB7A 表达上调，ZBTB7A 表达与 TNF、IL-6、TG、T-CHO 和 MDA 呈正相关。ZBTB7A 在肝细胞中高表达。OA 诱导的 ZBTB7A 表达与 SREBP1c 密切相关。ZBTB7A 可激活 SREBP1 启动子活性并激活 NF-B 活性。有趣的是，在 HepG2 细胞中获得了 ZBTB7A 在 SREBP1 启动子上的直接结合。抑制 ZBTB7A 表达可减轻 OA 诱导的脂质积聚，抑制脂肪生成相关基因和脂肪酸转运体基因的表达，促进氧化代谢相关基因的表达。
结论
ZBTB7A 在 NAFLD 的发展过程中起重要作用，肥胖诱导的 ZBTB7A 上调通过激活 SREBP1 和 NF-B 促进脂质积聚。ZBTB7A 可能是治疗 NAFLD 的一个潜在新靶点。
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